Tayebeh Hadizad

18F-FDG Cell Labeling May Underestimate Transplanted Cell Homing: More Accurate, Efficient, and Stable Cell Labeling with Hexadecyl-4-[18F]Fluorobenzoate for in Vivo Tracking of Transplanted Human Progenitor Cells by Positron Emission Tomography:

Cell therapy is expected to restore perfusion and improve function in the ischemic/infarcted myocardium; however, the biological mechanisms and local effects of transplanted cells remain unclear. To assess cell fate in vivo, hexadecyl-4-[18F]fluorobenzoate (18F-HFB) cell labeling was evaluated for tracking human circulating progenitor cells (CPCs) with positron emission tomography (PET) and was compared to the commonly used 2-[18F]fluoro-2-deoxy-d-glucose (18F-FDG) labeling method in a rat myocardial infarction model. CPCs were labeled with 18F-HFB or 18F-FDG ex vivo under the same conditions. 18F-HFB cell-labeling efficiency (23.4 ± 7.5%) and stability (4 h, 88.4 ± 6.0%) were superior to 18F-FDG (7.6 ± 4.1% and 26.6 ± 6.1%, respectively; p < 0.05). Neither labeling approach significantly altered cell viability, phenotype or migration potential up to 24 h postlabeling. Two weeks after left anterior descending coronary artery ligation, rats received echo-guided intramyocardial injection in the infarct border zone with 18F-HFB-CPCs, 18F-FDG-CPCs, 18F-HFB, or 18F-FDG. Dynamic PET imaging of both 18F-HFB-CPCs and 18F-FDG-CPCs demonstrated that only 16–37% of the initial injection dose (ID) was retained in the injection site at 10 min postdelivery, and remaining activity fell significantly over the first 4 h posttransplantation. The 18F-HFB-CPC signal in the target area at 2 h (23.7 ± 14.7% ID/g) and 4 h (17.6 ± 13.3% ID/g) postinjection was greater than that of 18F-FDG-CPCs (5.4 ± 2.3% ID/g and 2.6 ± 0.7% ID/g, respectively; p < 0.05). Tissue biodistribution confirmed the higher radioactivity in the border zone of 18F-HFB-CPC rats. Immunostaining of heart tissue sections revealed no significant difference in cell retention between two labeled cell transplantation groups. Good correlation with biodistribution results was observed in the 18F-HFB-CPC rats (r = 0.81, p < 0.05). Compared to 18F-FDG, labeling human CPCs with 18F-HFB provides a more efficient, stable, and accurate way to quantify the distribution of transplanted cells. 18F-HFB cell labeling with PET imaging offers a better modality to enhance our understanding of early retention, homing, and engraftment with cardiac cell therapy.

Novel O-[11C]methylated derivatives of candesartan as angiotensin II AT1 receptor imaging ligands: Radiosynthesis and ex vivo evaluation in rats

[(11)C]Methyl-candesartan and its desethyl derivative ([(11)C]TH4) were developed as potential radiotracers for imaging angiotensin II (Ang II) type 1 (AT(1)) receptors. These compounds were synthesized via methylation of tetrazole-protected candesartan using [(11)C]methyl iodide followed by deprotection through HCl hydrolysis at 65 degrees C to produce [(11)C]methyl-candesartan, and 90 degrees C for [(11)C]TH4. Ex vivo biodistribution and competition studies were carried out for both [(11)C]methyl-candesartan and [(11)C]TH4 to assess tissue retention time course and binding selectivity. Besides the liver, [(11)C]methyl-candesartan and [(11)C]TH4 displayed highest tissue retention in the AT(1) receptor-rich renal cortex and outer medulla. At tracer doses 15 min post-injection, [(11)C]methyl-candesartan demonstrated higher specific binding proportion for AT(1) receptors, and selectivity for AT(1) over Ang II AT(2), Mas, beta-adrenergic, and alpha(2)-adrenergic receptors in rat kidneys compared to [(11)C]TH4. This study indicates that [(11)C]methyl-candesartan has potential for in vivo imaging renal AT(1) receptors selectively using positron emission tomography.

Effecient synthesis and decomposition study of optically nonlinear adducts of tetracyanoquinodimethane

Abstract Described are the synthetic conditions resulting in a significant improvement in both yield and reaction time of Z -β-(1-substituted-4-pyridinium)-α-cyano-4-styryldicyanomethanide chromophores. A decomposition study of the zwitterionic chromophores in solution is also described.

PET imaging of a collagen matrix reveals its effective injection and targeted retention in a mouse model of myocardial infarction.

Injectable biomaterials have shown promise for cardiac regeneration therapy. However, little is known regarding their retention and distribution upon application in vivo. Matrix imaging would be useful for evaluating these important properties. Herein, hexadecyl-4-[(18)F]fluorobenzoate ((18)F-HFB) and Qdot labeling was used to evaluate collagen matrix delivery in a mouse model of myocardial infarction (MI). At 1 wk post-MI, mice received myocardial injections of (18)F-HFB- or Qdot-labeled matrix to assess its early retention and distribution (at 10 min and 2h) by positron emission tomography (PET), or fluorescence imaging, respectively. PET imaging showed that the bolus of matrix at 10 min redistributed evenly within the ischemic territory by 2h. Ex vivo biodistribution revealed myocardial matrix retention of ∼ 65%, which correlated with PET results, but may be an underestimate since (18)F-HFB matrix labeling efficiency was ∼ 82%. For covalently linked Qdots, labeling efficiency was ∼ 96%. Ex vivo Qdot quantification showed that ∼ 84% of the injected matrix was retained in the myocardium. Serial non-invasive PET imaging and validation by fluorescence imaging confirmed the effectiveness of the collagen matrix to be retained and redistributed within the infarcted myocardium. This study identifies matrix-targeted imaging as a promising modality for assessing the biodistribution of injectable biomaterials for application in the heart.

Analysis of [11C]methyl-candesartan kinetics in the rat kidney for the assessment of angiotensin II type 1 receptor density in vivo with PET ☆

INTRODUCTION Angiotensin II type 1 (AT(1)) receptors play a key role in the regulation of renal and cardiovascular functions and have been implicated in the pathogenesis of many diseases. The aim of this study was to assess binding of the novel radioligand [(11)C]methyl-candesartan to AT(1) receptors in the rat kidney in vivo with PET. METHODS Dynamic PET images were acquired for 60 min at baseline, with coinjection of candesartan (5 mg/kg), and after injection of PD123,319 (5 mg/kg). Volumes of distribution (R(C)∙V(T)) were estimated with a two-compartment model, by Logan analysis, and by taking the tissue-to-plasma activity ratio at 50-60 min post-injection. RESULTS The two-compartment model did not describe the kinetics at baseline adequately and the baseline scans were too short to obtain accurate estimates of R(C)∙V(T) with the Logan approach. Based on the tissue-to-plasma ratios, roughly one-third of V(T) at baseline could be attributed to AT(1) receptor binding. There were no indications of AT(2) receptor binding in the rat kidney. CONCLUSION It may be possible to detect changes in AT(1) receptor density in the rat kidney in vivo with [(11)C]methyl-candesartan and PET. Imaging AT(1) receptors with PET may provide valuable information on the role of these receptors in the pathogenesis of diseases such as hypertension, diabetic nephropathy, ventricular remodeling, and heart failure.

Synthesis and evaluation of the novel 2-[18F]fluoro-3-propoxy-triazole-pyridine-substituted losartan for imaging AT1 receptors

The 2-[(18)F]fluoro-3-pent-4-yn-1-yloxypyridine ([(18)F]FPyKYNE) analog of the potent non-peptide angiotensin II type 1 receptor (AT1R) blocker losartan was produced via click chemistry linking [(18)F]FPyKYNE to azide-modified tetrazole-protected losartan followed by TFA deprotection. Preliminary small animal imaging with positron emission tomography (PET) in rats displayed high uptake in the kidneys with good contrast to surrounding tissue. Rat metabolism displayed the presence of 23% unchanged tracer in plasma at 30 min. Upon co-administration with AT₁R blocker candesartan (2.5, 5 and 10 mg/kg), a dose-dependent reduction (47-65%) in tracer uptake was observed in the kidney, while no difference was observed following AT₂R blocker PD123,319 (5 mg/kg), indicating binding selectivity for AT₁R over AT₂R and potential for imaging AT₁R using PET.

Hole mobility and electroluminescence properties of a dithiophene indenofluorene

The development of organic laser diodes requires the availability of organic thin films that can attain high mobility without luminescence quenching. A dithiophene-substituted indenofluorene compound was designed as a compromise between luminous efficiency and mobility and has been studied in organic light-emitting diode and organic field-effect transistor devices. A relatively high luminous efficiency of 1cd∕A at a luminance of 1400cd∕m2 and a hole field-effect mobility of 1.2×10−2cm2∕Vs are reported in those two respective devices.

Characterization of [18F]FPyKYNE-losartan for Imaging AT1 Receptors

Most physiologic effects of the renin angiotensin system (RAS) are mediated via the angiotensin (Ang) type 1 receptor (AT1R). The 18F-FPyKYNE derivative of the clinically used AT1R blocker losartan exhibits high binding selectivity for kidney AT1R and rapid metabolism in rats. The aim of this study was to further assess the binding profile of this novel PET agent for imaging AT1R in rats and pigs. Methods: In vitro binding assays were performed with 18F-FPyKYNE-losartan in rat kidneys. Male Sprague–Dawley rats were used to assess dosimetry, antagonistic efficacy via blood pressure measurements, and presence of labeled metabolites in kidneys. Test–retest PET imaging, blocking with AT1R antagonist candesartan (10 mg/kg), and plasma metabolism analysis were performed in female Yorkshire pigs. Results: 18F-FPyKYNE-losartan bound with high affinity (dissociation constant of 49.4 ± 18.0 nM and maximal binding of 348 ± 112 fmol/mm2) to rat kidney AT1R. It bound strongly to plasma proteins in rats (97%), and its labeled metabolites displayed minimal interference on renal AT1R binding. FPyKYNE-losartan fully antagonized the Ang II pressor effect, albeit with 4-fold potency reduction (the effective dose inhibiting 50% of the Ang II–induced maximal pressor response of 25.5 mg/kg) relative to losartan. PET imaging exhibited high kidney-to-blood contrast and slow renal clearance, with an SUV of 14.1 ± 6.2. Excellent reproducibility was observed in the calculated test–retest variability (7.2% ± 0.75%). Only hydrophilic-labeled metabolites were present in plasma samples, and renal retention was reduced (−60%) at 10–15 min after blockade with candesartan. Conclusion: 18F-FPyKYNE-losartan has a favorable binding profile and displays high potential for translational work in humans as an AT1R PET imaging agent.

Evaluation of [11C]methyl-losartan and [11C]methyl-EXP3174 for PET imaging of renal AT1receptor in rats

INTRODUCTION The angiotensin II type 1 receptor (AT1R) is responsible for the main effects of the renin-angiotensin system (RAS), and its expression pattern is altered in several diseases. The [(11)C]methylated derivatives of the clinically used AT1R blocker (ARB) losartan and its active metabolite EXP3174, that binds with higher affinity to AT1R, were evaluated as potential PET imaging tracers in rat kidneys. METHODS [(11)C]Methyl-losartan and [(11)C]methyl-EXP3174 were synthesized by [(11)C]methylation of the tetrazole-protected analogs using [11C]methyl iodide. Tissue uptake and binding selectivity of [(11)C]methyl-losartan were assessed by ex-vivo biodistribution and in-vitro autoradiography. Radiolabeled metabolites in rat plasma and kidneys were analysed by column-switch HPLC. Both tracers were evaluated with small animal PET imaging. Due to better pharmacokinetics, [(11)C]methyl-EXP3174 was further investigated via PET by co-injection with AT1R antagonist candesartan or the AT2R antagonist PD123,319. RESULTS Binding selectivity to renal AT1 over AT2 and Mas receptors was demonstrated for [(11)C]methyl-losartan. Plasma metabolite analysis at 10 min revealed stability of [(11)C]methyl-losartan and [(11)C]methyl-EXP3174 with the presence of unchanged tracer at 70.8 ± 9.9% and 81.4 ± 6.0%, of total radioactivity, respectively. Contrary to [(11)C]methyl-losartan, co-injection of candesartan with [(11)C]methyl-EXP3174 reduced the proportion of unchanged tracer (but not metabolites), indicating that these metabolites do not bind to AT1R in rat kidneys. MicroPET images for both radiotracers displayed high kidney-to-background contrast. Candesartan significantly reduced [(11)C]methyl-EXP3174 uptake in the kidney, whereas no difference was observed following PD123,319 indicating binding selectivity for AT1R. CONCLUSIONS [(11)C]Methyl-EXP3174 displayed a favorable binding profile compared to [(11)C]methyl-losartan for imaging renal AT1Rs supporting further studies to assess its full potential as a quantitative probe for AT1R via PET.

Treatment with enalapril and not diltiazem ameliorated progression of chronic kidney disease in rats, and normalized renal AT1 receptor expression as measured with PET imaging

ACE inhibitors are considered first line of treatment in patients with many forms of chronic kidney disease (CKD). Other antihypertensives such as calcium channel blockers achieve similar therapeutic effectiveness in attenuating hypertension-related renal damage progression. Our objective was to explore the value of positron emission tomography (PET) imaging of renal AT1 receptor (AT1R) to guide therapy in the 5/6 subtotal-nephrectomy (Nx) rat model of CKD. Ten weeks after Nx, Sprague-Dawley rats were administered 10mg/kg/d enalapril (NxE), 30mg/kg/d diltiazem (NxD) or left untreated (Nx) for an additional 8–10 weeks. Kidney AT1R expression was assessed using in vivo [18F]fluoropyridine-losartan PET and in vitro autoradiography. Compared to shams, Nx rats exhibited higher systolic blood pressure that was reduced by both enalapril and diltiazem. At 18–20 weeks, plasma creatinine and albuminuria were significantly increased in Nx, reduced to sham levels in NxE, but enhanced in NxD rats. Enalapril treatment decreased kidney angiotensin II whereas diltiazem induced significant elevations in plasma and kidney levels. Reduced PET renal AT1R levels in Nx were normalized by enalapril but not diltiazem, and results were supported by autoradiography. Reduction of renal blood flow in Nx was restored by enalapril, while no difference was observed in myocardial blood flow amongst groups. Enhanced left ventricle mass in Nx was not reversed by enalapril but was augmented with diltiazem. Stroke volume was diminished in untreated Nx compared to shams and restored with both therapies. [18F]Fluoropyridine-Losartan PET allowed in vivo quantification of kidney AT1R changes associated with progression of CKD and with various pharmacotherapies.